CN117017967A - Application of tributyrin and tributyrin derivative in preparation of medicine for preventing and/or treating digestive tract complications caused by radiotherapy - Google Patents
Application of tributyrin and tributyrin derivative in preparation of medicine for preventing and/or treating digestive tract complications caused by radiotherapy Download PDFInfo
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- 238000001959 radiotherapy Methods 0.000 title claims abstract description 27
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- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
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Abstract
The invention relates to application of tributyrin and derivatives thereof in preparing medicines for preventing and/or treating digestive tract complications caused by radiotherapy, and belongs to the technical field of biological medicines. According to animal level experiments, the tributyrin and the tributyrin derivative disclosed by the invention are used for improving pathological phenomena such as mucosal ulcer edema, crypt distortion, inflammatory cell infiltration, submucosal thickening and the like caused by radiotherapy, and can be used for stimulating intestinal crypt cell proliferation and differentiation, promoting damaged colon repair after radiation and maintaining the integrity of intestinal mucosa barrier, so that digestive tract complications caused by radiotherapy are treated.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of tributyrin and derivatives thereof in preparing medicines for preventing and/or treating digestive tract complications caused by radiotherapy.
Background
The radiation enteropathy (Radiation Enteropathy, RE) refers to radiation intestinal injury caused by radiation treatment of a patient with pelvic cavity malignant tumor, and is usually taken as a demarcation point between an acute-phase lesion and a chronic-phase lesion 3 months after radiation, wherein the incidence rate of the acute-phase lesion is about 75%, and the incidence rate of the chronic-phase lesion is about 20%. Common symptoms of acute RE include diarrhea, abdominal pain, tenesmus, etc., most of which are self-limiting; part of symptoms persist and develop into chronic RE, so that blood is the main characteristic, and complications such as intestinal obstruction, intestinal perforation, intestinal fistula and the like occur in severe cases. The main pathological characteristics of RE include erosion and edema of intestinal mucosa, inflammatory infiltration, abnormal hyperplasia of blood vessels, fibrosis of intestinal wall and the like, and are closely related to the occurrence and development of symptoms such as rectal bleeding of RE. Despite the high incidence of RE, the specific mechanism by which it occurs and develops is not yet known, and there is currently a lack of clinically effective treatment regimens.
Short chain fatty acids (Short Chain Fatty Acids, SCFAs) are produced by anaerobic bacterial breakdown of insoluble cellulose at the colon site to provide nutrition to intestinal epithelial cells, with butyric acid being the predominant SCFA productivity. Studies show that butyric acid and sodium butyrate solution can promote intestinal epithelial cell proliferation, inhibit inflammatory infiltration, and maintain the integrity of intestinal mucosa barrier. However, in clinical practice, the therapeutic effect of the enema treatment of butyric acid and sodium butyrate on RE is greatly controversial. Although vernier P et al found that sodium butyrate enema could alleviate symptoms of acute radiation enteritis (vernier, P., et al. Clinical butyrate for acute radiation proctitis: random, cross-server three.Lancet 356,1232-1235 (2000)), the sample size of this queue was small and the extrapolation of the results was limited. A recent multi-center large-scale clinical study showed that continuous sodium butyrate enema treatment 2 weeks after irradiation had no significant effect on the incidence, severity and duration of radiation enteritis (Maggio, A., et al Daily sodium butyrate enema for the prevention of radiation proctitis in prostate cancer patients undergoing radical radiation therapy: results of a multicenter randomized placebo-controlled dose-defining phase 2 study). Butyric acid and sodium butyrate have poor effects in the treatment of clinical radioactive enteropathy, on the one hand, because all the ingested butyric acid and most of sodium butyrate are absorbed by the small intestine, and the concentration of the butyric acid and most of sodium butyrate actually entering the colon to play an anti-inflammatory and pro-prosthetic role is very low; on the other hand, the smell of the butyric acid and the sodium butyrate has the irritation, the enema operation is complex, the effective in vivo acting time is short, and the acceptance and the compliance of treatment are greatly limited. Thus, there is a need to mine other butyric acid for alternative drugs to drive treatment of RE.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide tributyrin and derivatives thereof which can relieve digestive tract complications caused by radiotherapy, and the tributyrin and derivatives thereof can be applied to the preparation of medicines for preventing and/or treating digestive tract complications caused by radiotherapy.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in a first aspect, the invention provides the use of tributyrin and derivatives thereof in the manufacture of a medicament for the prevention and/or treatment of digestive tract complications caused by radiotherapy.
Animal level experiments prove that tributyrin and the tributyrin derivatives can effectively relieve intestinal mucosa ulcer edema, crypt distortion, inflammatory cell infiltration and submucosal thickening caused by radiotherapy, and effectively treat digestive tract complications caused by radiotherapy.
Tributyrin (tributyrin) is an ester of butyric acid, which is catalytically decomposed by esterases in colon epithelial cells into 1 molecule of glycerol and 3 molecules of butyric acid. As a prodrug of butyric acid, tributyrin is released slowly in the intestinal tract, and is readily enriched in the colon. Studies have shown that tributyrin has a similar rate of penetration to sodium butyrate in colon epithelial cells, and that the former releases butyrate to exert a 3-fold effect on promoting cell proliferation and repair at the same concentration. Meanwhile, the tributyrin has no pungent smell, no toxic or side effect and good tolerance in animals and human bodies.
As a preferred embodiment of the use according to the present invention, the medicament for preventing and/or treating digestive tract complications caused by radiotherapy is a medicament for preventing and/or treating radiation intestinal diseases.
As a preferred embodiment of the application of the present invention, the tributyrin derivative includes at least one of butyric acid monoester, butyric acid diester, β -hydroxybutyric acid, butyric acid glyceride, dibutyrin, triacetin, acetate glyceride, diacetin, tripropionin, acetoacetic acid.
As a preferred embodiment of the use according to the invention, the tributyrin and its derivatives represent 20% of the total weight of the medicament for preventing and/or treating digestive tract complications caused by radiotherapy.
As a preferred embodiment of the use according to the invention, the tributyrin and its derivatives are present in solid or liquid form.
As a preferred embodiment of the use according to the invention, the tributyrin and its derivatives stimulate intestinal crypt cells to proliferate and differentiate, promote repair of the colon after irradiation, and maintain the integrity of the intestinal mucosal barrier.
As a preferred embodiment of the use according to the invention, the tributyrin and its derivatives inhibit inflammatory cell infiltration.
As a preferred embodiment of the application of the present invention, the dosage form of the drug for preventing and/or treating digestive tract complications caused by radiotherapy is at least one of capsules, tablets, oral preparations, microcapsule preparations, injections, suppositories, sprays, ointments, gels, solutions, powders, lotions, tinctures, oils, creams and aerosols.
As a preferred embodiment of the use according to the invention, the route of administration of the medicament for the prophylaxis and/or treatment of digestive complications caused by radiotherapy comprises at least one of oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual and rectal means.
In a second aspect, the present invention provides a medicament for the treatment of digestive tract complications caused by radiotherapy, said medicament comprising tributyrin and its derivatives and a pharmaceutically acceptable carrier.
Compared with the prior art, the invention has the beneficial effects that:
according to animal level experiments, the tributyrin and the tributyrin derivative have the advantages of improving mucosal ulcer edema, crypt distortion, inflammatory cell infiltration and submucosal thickening caused by radiotherapy, adjusting intestinal flora balance and assisting in resisting oxidative damage caused by radiotherapy, so that digestive tract complications caused by radiotherapy are treated.
Drawings
FIG. 1 is a dosing regimen for mice in experimental examples;
FIG. 2 shows HE staining results of each experimental group in experimental examples;
fig. 3 shows the histopathological score (RIS) of radiation intestinal injury for each experimental group in the experimental example, where "×" indicates that there is a statistical difference between the two groups, p < 0.001, and "n.s." indicates that there is no statistical difference between the two groups.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the following specific examples.
The reagents and consumables used in the following examples were all commercially available without any particular explanation.
Healthy male SPF grade C57BL/6J mice were supplied by Jiangsu Ji Yikang Biotechnology Co.
The experimental mouse maintenance feed is provided by the company of the Co-ordinated medical bioengineering Co.
Experimental example
In order to verify the treatment effect of tributyrin and its derivatives in digestive tract complications caused by radiotherapy, the effect of tributyrin and its derivatives in treating radiation intestinal diseases is evaluated by animal experiments, and the specific scheme is as follows:
(1) Animal model selection and grouping
C57BL/GJ male mice weighing 16-18g were selected and randomly divided into 3 groups of 10 animals each. The experiments were set up in 3 groups and the specific treatments are shown in table 1.
Table 1 treatment of each experimental group
| Group of | Drug treatment |
| Control group | Normal laboratory mice maintenance feedMaterial |
| Tributyrin group | Experimental mouse maintenance feed containing 20% (g/g) tributyrin |
| Sodium butyrate group | Experimental mouse maintenance feed containing 20% (g/g) sodium butyrate |
(2) Drug treatment
As shown in fig. 1, the mice were continuously fed with feeds grouped according to table 1 for 2 weeks, and the mice were partially irradiated with X-rays on the pelvis, specifically as follows: the day of irradiation was anesthetized by intraperitoneal injection of 1% sodium pentobarbital solution at an anesthetic dose of 40mg/kg. The anesthetized mouse is horizontally placed in a lead box with the length of 3.5 multiplied by 6cm, the lower edge of a lead cover which is slidable above the lead box is moved to a position of about 1cm above the anus of the mouse, the anus of the mouse and a section of 1cm of intestine above the anus are exposed in an X-ray irradiation range, the lead box is placed in an RS2000 small animal radiometer for irradiation, the total radiation dose is set to be 25Gy, and the dose rate is set to be 2.95Gy/min.
After the irradiation, after the mice were naturally recovered, the mice were fed with feeds, which were grouped in Table 1, for 8 weeks continuously, and the state of the mice was observed daily, and the weights were weighed daily.
(3) Detection of the conditions of the radioactive intestine of mice
After X-ray irradiation, the mice were continuously fed to week 8, cervical dislocation was sacrificed, the colon of the mice was taken out, the anus and the colorectal 1cm above were cut with reference to the rigid ruler, the split bowel was divided longitudinally into 2 equal parts, 1 part was used to make pathological sections, and placed in 1ml of 4% neutral formalin, followed by HE staining.
The specific steps of HE staining are as follows: taking out colorectal tissue placed in 4% neutral formalin fixed liquid for 24 hours, washing with running water, dehydrating, transparent, embedding paraffin, preparing into continuous paraffin sections with the size of 4 mu m, dewaxing, dehydrating, dying hematoxylin at room temperature for 10min, washing for 30s, differentiating 1% hydrochloric acid alcohol for 3s, washing for 1min, dying eosin at room temperature for 5-10min, dehydrating with gradient alcohol, transparent xylene and sealing with neutral resin. The HE staining results are shown in FIG. 2.
The radioactive intestinal injury histopathological scoring (RIS) was performed according to HE-stained sections, the scoring details are shown in table 2, and the scoring results are shown in fig. 3.
As shown in fig. 2-3, compared with the mice in the control group, the intestinal tissue pathological damage of the mice in the tributyrin group is obviously reduced, and the RIS score is obviously reduced, and the mice are particularly characterized by mucosa ulcer edema, crypt distortion, inflammatory cell infiltration and obvious thickening of submucosa in the control group; the tributyrin group mice have no obvious edema in the mucous membrane layer, slight erosion and limitation to the surface layer, the intestinal epithelial cells are orderly arranged, the intestinal crypt has no obvious distortion, the inflammatory infiltration is slight and limitation to the lamina propria, and no obvious fibrosis is found in the submucosa.
Compared with the mice in the control group, the mice in the sodium butyrate group can not effectively reduce the degree of the lesion, and RIS of the two groups has no obvious difference, and the mice in the sodium butyrate group are particularly characterized by mucosal erosion, crypt distortion, inflammatory cell infiltration and obvious thickening of submucosa in the control group; sodium butyrate group mucosal layer erosion edema, almost total loss of crypt, inflammatory cells infiltrate into lamina propria, collagen fibrous glass-like degeneration of submucosa.
The results show that the tributyrin can play a role in treating the radiation enteropathy by stimulating proliferation and differentiation of intestinal crypt cells, promoting colon repair after radiation and maintaining the integrity of intestinal mucosa barrier, simultaneously inhibiting inflammatory cell infiltration, regulating intestinal flora balance and assisting in resisting oxidative damage caused by radiation therapy.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted equally without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. The tributyrin and the derivative thereof are applied to the preparation of medicines for preventing and/or treating digestive tract complications caused by radiotherapy.
2. The use according to claim 1, wherein the medicament for preventing and/or treating digestive tract complications caused by radiotherapy is a medicament for preventing and/or treating radiation enteropathy.
3. The use of claim 1, wherein the tributyrin derivative comprises at least one of monobutyrate, dibutyrate, β -hydroxybutyrate, dibutyrate, triacetin, glyceryl acetate, glyceryl diacetate, glyceryl tripropionate, acetoacetate.
4. The use according to claim 1, wherein said tributyrin and derivatives thereof constitute 20% of the total weight of the medicament for preventing and/or treating radiation-induced complications of the digestive tract.
5. The use according to claim 1, wherein the tributyrin and its derivatives are in solid or liquid form.
6. The use according to claim 1, wherein said tributyrin and derivatives thereof stimulate intestinal crypt cell proliferation and differentiation, promote post-irradiation damaged colonic repair and maintain intestinal mucosal barrier integrity.
7. The use of claim 1, wherein said tributyrin and derivatives thereof inhibit inflammatory cell infiltration.
8. The use according to claim 1, wherein the medicament for preventing and/or treating digestive tract complications caused by radiotherapy is in the form of at least one of capsules, tablets, oral preparations, microcapsule preparations, injections, suppositories, sprays, ointments, gels, solutions, powders, lotions, tinctures, oils, creams and aerosols.
9. The use according to claim 1, wherein the route of administration of the medicament for the prophylaxis and/or treatment of digestive complications caused by radiotherapy comprises at least one of oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual and rectal means.
10. A medicament for treating digestive tract complications caused by radiotherapy, which is characterized by comprising tributyrin and derivatives thereof and a pharmaceutically acceptable carrier.
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| CN202311114828.5A CN117017967A (en) | 2023-08-31 | 2023-08-31 | Application of tributyrin and tributyrin derivative in preparation of medicine for preventing and/or treating digestive tract complications caused by radiotherapy |
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| CN202311114828.5A CN117017967A (en) | 2023-08-31 | 2023-08-31 | Application of tributyrin and tributyrin derivative in preparation of medicine for preventing and/or treating digestive tract complications caused by radiotherapy |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5569680A (en) * | 1995-02-13 | 1996-10-29 | Trustees Of The Univ. Of Penna | Method of treating inflammatory bowel disease with tributyrin |
| CN1843508A (en) * | 2005-04-07 | 2006-10-11 | 安成制药科技股份有限公司 | A composition for treating gastrointestinal distress |
| US9668991B1 (en) * | 2015-12-09 | 2017-06-06 | International Business Machines Corporation | SCFA colonic composition |
| CN112826814A (en) * | 2020-12-22 | 2021-05-25 | 中山大学附属第六医院 | Use of 3-hydroxybutyric acid or derivatives thereof or bacterial compositions producing same for the treatment of radiation-induced intestinal lesions |
-
2023
- 2023-08-31 CN CN202311114828.5A patent/CN117017967A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5569680A (en) * | 1995-02-13 | 1996-10-29 | Trustees Of The Univ. Of Penna | Method of treating inflammatory bowel disease with tributyrin |
| CN1843508A (en) * | 2005-04-07 | 2006-10-11 | 安成制药科技股份有限公司 | A composition for treating gastrointestinal distress |
| US9668991B1 (en) * | 2015-12-09 | 2017-06-06 | International Business Machines Corporation | SCFA colonic composition |
| CN112826814A (en) * | 2020-12-22 | 2021-05-25 | 中山大学附属第六医院 | Use of 3-hydroxybutyric acid or derivatives thereof or bacterial compositions producing same for the treatment of radiation-induced intestinal lesions |
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